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3. Protein C Inhibitor as a Diagnostic Marker: Immunohistochemical Expression in Prostatic Adenocarcinoma and Benign Prostatic Hyperplasia

Author

Liridon Selmani, Rinё Limani, Riaz Agahi, Ilir Hoxha, and Suzana Manxhuka Kёrliu

Subjects
prostate, cancer, biomarkers, protein c inhibitor, Medicine
Abstract

Background: This study explores the immunohistochemical expression of protein C inhibitor (PCI) in patients with prostatic adenocarcinoma (PCa) and benign prostatic hyperplasia (BPH). Methods and Results: Our study involved 56 prostate samples morphologically diagnosed as PCa and 30 BPH samples. An immunohistochemical analysis of the PCI expression was performed. Our analysis encompassed variables including age, serum prostate-specific antigen (PSA), local and distant metastasis, PCI staining, and morphological features such as Gleason Score and Grade Group. In addition to descriptive statistics, Spearman's rank correlation test was performed. All patients with BPH had no staining or low staining for PCI. 60% of PCa patients had moderate or strong staining intensity for PCI. There was no correlation between PCI expression and clinicopathological parameters, including PCI expression and PSA, Gleason Score, and Grade Group. A negative correlation was observed between age at diagnosis and PCI expression. Conclusion: Our study did not find a statistically significant correlation between PCI and PCa. However, we report that in 60% of our PCa cases, there is a moderate and high-intensity expression for PCI.

Published
2024
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10. COMPARISON OF PROTEIN C INHIBITOR (PCI) BLOOD LEVELS IN WOMEN BEFORE STARTING SECOND GENERATION ORAL CONTRACEPTIVE PILLS AND AFTER THREE MONTHS OF USE.

Author

Mahmood, Namra

Subjects
*PILLS, *PROTEIN C, *ORAL contraceptives, *TISSUE plasminogen activator, *PERCUTANEOUS coronary intervention, *CONVENIENCE sampling (Statistics)
Abstract

Background: Protein C inhibitor (PCI) is a serine protease inhibitor synthesized by the liver. Apart from its function of inhibiting activated protein C (APC), PCI also inhibits activated factor II, thrombin thrombomodulin complex, factor XIa, tissue plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA). Increased level of PCI has been found in patients with thrombosis and women using oral contraceptives. The aim of the present study is to observe the effect of combined oral contraceptive pills on PCI levels after three months of its use and mean change from baseline. Materials & Methods: Cross sectional descriptive study carried out at the pathology department, post graduate medical institute (PGMI) between 01/03/2018 to 02/03/2019 after taking ethical approval. Purposive convenience sampling technique was used. Blood sample of the study population was taken before the start of medication and after three menstrual cycles. Protein C inhibitor levels and demographic data was collected and analyzed using SPSS. Results: Among total 54 females, the age of the women ranged from 22 years to 44 years with a mean of 29.5 ±5.3 years. The parity of the women ranged from 1 to 6 with a mean of 3.06 ±1.20. The baseline value of protein C inhibitor levels ranged from 1.1 to 8.7 mg/l with a mean of 5.84 ± 1.83 mg/l at baseline and increased upon 3-months follow-up to 8.2 to 20.1 mg/l with a mean of 12.74 ±3.29 mg/l. The women aged 29-35 years had highest of PCI levels at follow up with a mean of 13.47 ±4.28 mg/l and primiparas had highest increase among groups and it was statistically significant (p-value < 0.001). Conclusion: It can be concluded from the study that use of the second generation oral contraceptive for 3 months is associated with induction of prothrombotic state by increase in the level of protein C inhibitor in the absence of any other prothrombotic conditions. [ABSTRACT FROM AUTHOR]

Published
2023
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12. Phosphoproteomic analysis of protease-activated receptor-1 biased signaling reveals unique modulators of endothelial barrier function

Author

Lin, Ying, Wozniak, Jacob M, Grimsey, Neil J, Girada, Sravan, Patwardhan, Anand, Molinar-Inglis, Olivia, Smith, Thomas H, Lapek, John D, Gonzalez, David J, and Trejo, JoAnn

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Hematology, HIV/AIDS, 2.1 Biological and endogenous factors, Aetiology, Calmodulin-Binding Proteins, Carrier Proteins, Endothelial Cells, Humans, Microfilament Proteins, Phosphorylation, Protein C Inhibitor, Proteomics, Receptor, PAR-1, Signal Transduction, Thrombin, actin, arrestin, GPCR, inflammation, thrombin
Abstract

Thrombin, a procoagulant protease, cleaves and activates protease-activated receptor-1 (PAR1) to promote inflammatory responses and endothelial dysfunction. In contrast, activated protein C (APC), an anticoagulant protease, activates PAR1 through a distinct cleavage site and promotes anti-inflammatory responses, prosurvival, and endothelial barrier stabilization. The distinct tethered ligands formed through cleavage of PAR1 by thrombin versus APC result in unique active receptor conformations that bias PAR1 signaling. Despite progress in understanding PAR1 biased signaling, the proteins and pathways utilized by thrombin versus APC signaling to induce opposing cellular functions are largely unknown. Here, we report the global phosphoproteome induced by thrombin and APC signaling in endothelial cells with the quantification of 11,266 unique phosphopeptides using multiplexed quantitative mass spectrometry. Our results reveal unique dynamic phosphoproteome profiles of thrombin and APC signaling, an enrichment of associated biological functions, including key modulators of endothelial barrier function, regulators of gene transcription, and specific kinases predicted to mediate PAR1 biased signaling. Using small interfering RNA to deplete a subset of phosphorylated proteins not previously linked to thrombin or APC signaling, a function for afadin and adducin-1 actin binding proteins in thrombin-induced endothelial barrier disruption is unveiled. Afadin depletion resulted in enhanced thrombin-promoted barrier permeability, whereas adducin-1 depletion completely ablated thrombin-induced barrier disruption without compromising p38 signaling. However, loss of adducin-1 blocked APC-induced Akt signaling. These studies define distinct thrombin and APC dynamic signaling profiles and a rich array of proteins and biological pathways that engender PAR1 biased signaling in endothelial cells.

Published
2020

25. A common protein C inhibitor exosite partially controls the heparin induced activation and inhibition of serine proteases.

Author

Siddiqui, Urfi, Khan, Abdul Burhan, Ahmad, Tahif, Rehman, Ahmed Abdur, and Jairajpuri, Mohamad Aman

Subjects
*THROMBIN receptors, *PROTEIN C, *BLOOD coagulation factor IX, *HEPARIN, *WESTERN immunoblotting, *THROMBIN
Abstract

Protein C inhibitor (PCI) maintains hemostasis by inhibiting both procoagulant and anticoagulant serine proteases, and plays important roles in coagulation, fibrinolysis, reproduction, and anti-angiogenesis. The reactive site loop of PCI traps and irreversibly inhibits the proteases like APC (activating protein C), thrombin (FIIa) and factor Xa (FXa). Previous studies on antithrombin (ATIII) had identified Tyr253 and Glu255 as functional exosites that interact and aid in the inhibition of factor IXa and FXa. Presence of exosite in PCI is not known, however a sequence comparison with the PCI from different vertebrate species and ATIII identified Glu239 to be absolutely conserved. PCI residues analogous to ATIII exosite residues were mutated to R238A and E239A. Purified variant PCI in the presence of heparin (10 μg/ml) showed a 2–4 fold decrease in the rate of inhibition of the proteases. However, the stoichiometry of inhibition of FIIa, APC, and FXa by native PCI, R238A and E239A variants were found to be close to 1.0, which also indicated the formation of stable complexes based on SDS-PAGE and western blot analysis with thrombin and APC. Our findings revealed the possible presence of an exosite in PCI that influences the protease inhibition rates. [ABSTRACT FROM AUTHOR]

Published
2024
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33. Activated protein C assays: A review.

Author

Oto, Julia, Fernández-Pardo, Álvaro, Miralles, Manuel, Plana, Emma, España, Francisco, Navarro, Silvia, and Medina, Pilar

Subjects
*PROTEIN C, *DISSEMINATED intravascular coagulation, *RECOMBINANT molecules
Abstract

• Assays to measure circulating APC will become of interest in the upcoming years. • The APC assays available are based on different strategies. • The performance of these available assays is quite different and should be used according to the clinical situation. Activated protein C (APC) acts as an "on demand" anticoagulant, reducing thrombin formation. Reduced plasma levels of APC or protein C (PC) are associated with an increased risk of venous thromboembolism. APC also displays cytoprotective functions and its therapeutic use has been evaluated in severe sepsis and is under evaluation in several diseases with an important inflammatory component. In addition, different studies have revealed a potential role of PC/APC in disorders such as obesity, pneumonia, disseminated intravascular coagulation, Alzheimer, stroke, etc. Accordingly, the therapeutic value of different recombinant APC molecules that lack anticoagulant activity but retain the cytoprotective function is being tested in clinical trials for some of these diseases. Therefore, an available method to measure circulating APC in plasma is of great interests. About 16 different methods for the quantification of APC have been reported. Here, we will review the available assays, highlighting their advantages and disadvantages as well as their different stages of implementation and the most appropriate use for each method, including their potential clinical usefulness. [ABSTRACT FROM AUTHOR]

Published
2020
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36. Therapeutic exosomes loaded with SERPINA5 attenuated endometrial cancer cell migration via the integrin β1/FAK signaling pathway

Author

Yunfeng Song, Lei Ye, Yuan Tan, Huan Tong, Zeheng Lv, Xiaoping Wan, and Yiran Li

Subjects
Cancer Research, Integrin beta1, General Medicine, Exosomes, Endometrial Neoplasms, MicroRNAs, Oncology, Cell Movement, Cell Line, Tumor, Humans, Molecular Medicine, Female, Signal Transduction, Cell Proliferation, Protein C Inhibitor
Abstract

Metastasis is still the major cause of endometrial cancer (EC)-related death. Because of their biological function and regenerative properties, exosomes have been applied to therapeutic regimens. SERPINA5 expression is downregulated in several tumors and linked to tumor cell migration and invasion. However, the expression and biological functions of SERPINA5 in EC remain unclear.The levels of SERPINA5 in plasma exosomes were determined with ELISAs. SERPINA5 expression in EC and its relationship with survival outcomes were analyzed using the TCGA database and clinical EC tissue samples. The effect of SERPINA5 overexpression or exosomal SERPINA5 on EC metastasis was examined by cell migration and invasion assays in vitro. Mechanistically, overexpression of SERPINA5 or high exosomal SERPINA5 levels mediated the regulation of the integrin β1/FAK signaling pathway in EC cell lines. The therapeutic effect of exosomal SERPINA5 was determined with xenograft models.This study revealed that the level of exosomal SERPINA5 was increased in the circulating plasma of EC patients. In addition, the expression of SERPINA5 was decreased in EC patients with distant metastasis, and low expression of SERPINA5 indicated worse survival. In addition, SERPINA5 was elevated in normal tissues adjacent to EC tumors. Moreover, overexpression of SERPINA5 inhibited metastatic potential of EC cell lines in vitro. Furthermore, SERPINA5 loaded on secreted exosomes reduced the metastatic ability of EC cells. Notably, overexpression of SERPINA5 or high exosomal SERPINA5 levels suppressed EC metastatic potential by suppressing integrin β1/FAK signaling pathway activation. Finally, exosomal SERPINA5 impeded tumor growth and metastasis in xenograft models.Our findings revealed that a low level of SERPINA5 expression indicated poor survival outcomes in EC and that exogenous SERPINA5 loading of exosomes may be a novel therapeutic strategy for metastatic EC.

Published
2022

38. SERPINA5 Protein in Cumulus-Oocyte Complexes Increases the Fertilisation Ability of Mouse Sperm

Author

Siyuan Cao, Zhang Qian, Ronghua Wu, Shanshan Sun, Jun Jing, Guangyun Zhang, Weiqing Chen, Yifeng Ge, Jinzhao Ma, Shuxian Wang, Lei Ouyang, Tongmin Xue, Dandan Wang, Shanmeizi Zhao, Kuan Liang, Xie Ge, Ying Lin, Li Chen, and Bing Yao

Subjects
Male, Proteomics, Sperm-Ovum Interactions, Mice, Inbred ICR, Obstetrics and Gynecology, Spermatozoa, Zona Pellucida Glycoproteins, Mice, Semen, Fertilization, Oocytes, Animals, Humans, Female, Sperm Capacitation, Zona Pellucida, Protein C Inhibitor
Abstract

Obtaining high-quality sperm is key to improving the success rate of assisted reproductive technology (ART). Although cytokines secreted by cumulus-oocyte complexes (COCs) bind to sperm surface receptors to improve sperm quality, the effects of adding mouse COCs to human tubal fluid (HTF) medium on sperm capacitation have not yet been explored. Eight-week-old ICR mouse COCs were added to HTF medium and crushed to obtain the post-modified HTF medium. Compared with using HTF medium, the fertilisation rate and number of sperm combined with the zona pellucida significantly increased after in vitro capacitation using the post-modified HTF medium (P 0.01). Proteomic and Western blotting analyses showed that the level of SERPINA5 in sperm increased significantly following in vitro capacitation with the post-modified HTF medium (P 0.05). Immunohistochemical staining analysis demonstrated that SERPINA5 protein was expressed in mouse cumulus cells. A SERPINA5 antibody was added in the post-modified HTF medium to block the effects of SERPINA5 after in vitro capacitation, which significantly decreased the fertilisation rate and the number of sperm combined with the zona pellucida (P 0.05). Recombinant mouse SERPINA5 protein (1 ~ 2 μg/ml) was added to HTF medium and the fertilisation rate and the number of sperm combined with the zona pellucida significantly increased (P 0.01). Moreover, recombinant human SERPINA5 protein (5 μg/ml) was added before human semen freezing. Compared with adding no SERPINA5 protein, the percentage of normal sperm morphology and the intact acrosome significantly increased (P 0.05). Our study provides a reference method for optimising sperm quality in the process of in vitro capacitation.

Published
2022

39. Evaluation the Presence of SERPINA5 (Exon 3) and FTO rs9939609 Polymorphisms in Papillary Thyroid Cancer Patients

Author

Mohammad Mandegari, Habib Fazel-Yazdi, Nasim Fazel-Yazdi, Ahmad Shirinzadeh-Dastgiri, Mohammad Rahim Vakili, and Seyed Mohammad Moshtaghioun

Subjects
Male, medicine.medical_specialty, endocrine system diseases, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Iran, Polymerase Chain Reaction, FTO gene, Papillary thyroid cancer, Exon, Polymorphism (computer science), Internal medicine, Genetic variation, medicine, Humans, Thyroid Neoplasms, SERPINA5 gene, Gene, Polymorphism, Single-Stranded Conformational, Protein C Inhibitor, Direct sequencing, business.industry, nutritional and metabolic diseases, Exons, General Medicine, medicine.disease, Endocrinology, Thyroid Cancer, Papillary, Case-Control Studies, Female, business
Abstract

Background A few researches evaluated the association of polymorphisms at SERPINA5 and fat mass and obesity-associated protein (FTO) genes with papillary thyroid cancer (PTC) globally. Here, we examined the presence of genetic variations within coding exon 3 of SERPINA5 gene and FTO rs9939609 polymorphism in Iranian PTC patients. Methods A total of 122 patients (42 cases for SERPINA5 and 80 cases for FTO gene) and 120 healthy subjects (40 subjects or SERPINA5 and 80 subjects for FTO gene) were recruited. The genetic variation within coding exon 3 of SERPINA5 gene was evaluated by reaction-single-strand conformation polymorphism (PCR-SSCP) and FTO rs9939609 polymorphism was evaluated by RFLP-PCR assay. Results The PCR-SSCP technique detected two rs6115G>A and rs6112T>C genetic variations within coding exon 3 of SERPINA5 gene and approved also by direct sequencing. For rs6112T>C polymorphism seven patients was heterozygous and for rs6115G>A seven PTC patients were heterozygous and two patients were homozygous. Conclusion This study indicated that SERPINA5 rs6115G>A and rs6112T>C polymorphisms might be a novel susceptibility locus for PTC in Iranian patients. However, our findings do not support an association between FTO rs9939609 polymorphism and PTC risk.

Published
2021

41. [Biochemical markers of thrombotic complications in the acute period of ischemic stroke]

Author

Anatoly G. Kochetov, Olga V. Lyang, Irina A. Zhirova, and Oleg O. Ivoylov

Subjects
Male, History, Endocrinology, Diabetes and Metabolism, Thrombomodulin, Thrombosis, Plasminogen, General Medicine, Urokinase-Type Plasminogen Activator, Antifibrinolytic Agents, Fibronectins, Tissue Plasminogen Activator, Plasminogen Activator Inhibitor 1, Humans, Female, Fibrinolysin, Vitronectin, Family Practice, Homocysteine, Biomarkers, Aged, Protein C Inhibitor, Ischemic Stroke
Abstract

To study the profile of biochemical markers of the hemostasis system, to clarify their role and relationships in the pathogenesis of the development of thrombotic complications (TC) of ischemic stroke (IS) and the associated assessment of the possibilities of their diagnostic application.The study group included 302 patients (164 men, 138 women) who were admitted to the hospital with a diagnosis of IS within 24 hours of the onset of the disease. The diagnosis was confirmed by computed tomography. The average age of patients was 69 (5088) years. Blood was taken from all patients on the 1st day of the disease to determine the profile of analytes presumably associated with the pathogenesis of TC. Levels of homocysteine, protein C inhibitor, thrombomodulin, plasminogen, tissue plasminogen activator, urokinase, plasminogen activator type 1 inhibitor, t-PA/PAI-1 complex, vitronectin, plasmin-2-antiplasmin complex, D-dimer, fibronectin were determined in blood serum by ELISA.TC in the acute period of IS (up to 21 days) were recorded in 32 (10.6%, 95% CI 7.3714.3) patients, of which pulmonary embolism was observed in 27 (8.94%, 95% CI 5.9812.4) patients, deep vein thrombosis in 5 (1.66%, 95% CI 0.473.47) patients. The results of the study of a panel of specific proteins involved in pathogenetic processes accompanying necrosis of brain tissue in IS demonstrated that of the entire list of markers of the hemostasis system activation selected for the study, the most significant are: the concentration of fibronectin in the prognosis of the absence of TC with a threshold value of more than 61 mkg/ml and OR 4.4 (95% CI 1.512.9, p=0.011), and the concentration of the t-PA/PAI-1 complex in the prognosis of the development of TC with a threshold value of more than 14 ng/ml and OR 11.3 (95% CI 1.18109.3, p=0.03).The significance of the t-PA/PAI-1 complex and fibronectin as markers of TC in IS may be due to a violation of the activation processes of the fibrinolytic link of hemostasis and the accumulation of non-deposited compounds that damage the vascular wall.Цель. Изучить профиль биохимических маркеров системы гемостаза для уточнения их роли и взаимоотношений в патогенезе развития тромботических осложнений (ТО) ишемического инсульта (ИИ) и связанной с этим оценки возможностей их диагностического применения. Материалы и методы. В группу исследования включены 302 пациента (164 мужчины, 138 женщин), поступивших в стационар с диагнозом ИИ в течение 24 ч от начала развития заболевания. Диагноз подтвержден методом компьютерной томографии. Средний возраст пациентов составлял 69 (5088) лет. У всех пациентов в 1-е сутки заболевания взята кровь для определения профиля аналитов, предположительно ассоциированных с патогенезом развития ТО. В сыворотке крови методом иммуноферментного анализа определены уровни гомоцистеина, ингибитора протеина С, тромбомодулина, плазминогена, тканевого активатора плазминогена, урокиназы, ингибитора активатора плазминогена 1-го типа, комплекса t-PA/PAI-1, витронектина, комплекса плазмин-2-антиплазмин, D-димера, фибронектина. Результаты. ТО в остром периоде ИИ (до 21 сут болезни) зафиксированы у 32 (10,6%, 95% доверительный интервал ДИ 7,3714,3) пациентов, из них тромбоэмболия легочной артерии отмечалась у 27 (8,94%, 95% ДИ 5,9812,4) пациентов, тромбоз глубоких вен у 5 (1,66%, 95% ДИ 0,473,47) пациентов. Исследование панели специфических белков, участвующих в патогенетических процессах, сопровождающих некроз ткани мозга при ИИ, продемонстрировало, что из всего выбранного для исследования перечня биохимических маркеров системы гемостаза наиболее значимы: концентрация фибронектина в прогнозе отсутствия ТО с пороговым значением более 61 мкг/мл и отношением шансов 4,4 (95% ДИ 1,512,9, р=0,011) и концентрация комплекса t-PA/PAI-1 в прогнозе развития ТО с пороговым значением более 14 нг/мл и отношением шансов 11,3 (95% ДИ 1,18109,3, р=0,03). Заключение. Значимость комплекса t-PA/PAI-1 и фибронектина как маркеров ТО при ИИ может быть обусловлена нарушением процессов активации фибринолитического звена гемостаза и накоплением неопсонированных соединений, повреждающих сосудистую стенку.

Published
2022

42. Identification of novel diagnostic biomarkers for deep venous thrombosis.

Author

Memon, Ashfaque A., Sundquist, Kristina, PirouziFard, Mirnabi, Elf, Johan L., Strandberg, Karin, Svensson, Peter J., Sundquist, Jan, and Zöller, Bengt

Subjects
*BIOLOGICAL tags, *VENOUS thrombosis, *PROTEIN C inhibitor, *SERPINS, *OSTEOPONTIN
Abstract

Summary: The combination of a negative D‐dimer and a Wells score can rule out, but not confirm, a diagnosis of deep venous thrombosis (DVT). We aimed to identify new diagnostic biomarkers for DVT and to investigate their relationship with hypercoagulability markers [D‐dimer and activated protein C‐protein C inhibitor (APC‐PCI) complex]. We screened 92 cardiovascular‐specific proteins in plasma samples from 45 confirmed DVT patients and 45 age‐ and sex‐matched non‐DVT patients selected from a prospective multicentre diagnostic management study (SCORE) by Proseek Multiplex CVDIII96×96. Plasma levels of 30 proteins were significantly different between DVT and non‐DVT patients. After Bonferroni correction, plasma levels of seven proteins: P‐selectin, transferrin receptor protein 1, von Willebrand factor, tissue factor pathway inhibitor, osteopontin (OPN), bleomycin hydrolase and ST2 protein remained significantly different. The area under curve (AUC) for these proteins ranged from 0·70 to 0·84. Furthermore, all seven identified proteins were significantly associated with markers of hypercoagulability. A combination of OPN and APC‐PCI had the best ability to discriminate DVT from non‐DVT patients (AUC = 0·94; sensitivity = 89% and specificity = s84%). In conclusion, we identified multiple proteins associated with markers of hypercoagulability and with a potential to become novel diagnostic biomarkers for DVT. [ABSTRACT FROM AUTHOR]

Published
2018
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43. ANXA2, SP17, SERPINA5, PRDX2 genes, and sperm DNA fragmentation differentially represented in male partners of infertile couples with normal and abnormal sperm parameters

Author

Maliheh, Afsari, Farzaneh, Fesahat, Ali Reza, Talebi, Ashok, Agarwal, Ralf, Henkel, Fatemeh, Zare, Murat, Gül, Nunzio, Iraci, Rossella, Cannarella, Masoud, Makki, Morteza, Anvari, Abolghsem Abbasi, Sarcheshmeh, and Amir Hossein, Talebi

Subjects
Male, Membrane Proteins, DNA Fragmentation, Peroxiredoxins, Spermatozoa, Antioxidants, Semen, Humans, Calmodulin-Binding Proteins, RNA, Messenger, Annexin A2, Biomarkers, Infertility, Male, Protein C Inhibitor
Abstract

This study aims to evaluate the expression of genes associated with the fertilisation potential and embryo development, sperm DNA fragmentation (SDF), and acrosome reaction in male partners of infertile couples with different sperm parameters compared to fertile men. First, male partners of infertile couples with abnormal (N = 25) and normal sperm parameters (N = 25), and fertile men (N = 10) were included in experimental groups I, II, and controls respectively. The mRNA levels of the Annexin A2 (ANXA2), Sperm protein 17 (SP17), Plasma serine protease inhibitor (SERPINA5), and Peroxiredoxin-2 (PRDX2) genes and SDF were evaluated. To evaluate the maturity of the sperm and oxidative stress, the acrosome reaction, the lipid peroxidation, and total antioxidant were measured. As result, SP17 showed a significantly lower expression in both experimental groups. SERPINA5 was significantly down-regulated in experimental group I that was aligned with the low rate of acrosome reaction. Significant overexpression of PRDX2 was found between experimental group II and controls. Significant higher rates of SDF were seen in both experimental groups compared to the controls. Finally, our data suggest that differentially gene expression of SP17 is a potential diagnostic biomarker in infertile men either with normal or abnormal sperm parameters. SDF is one of the causes of male infertility, independent of the sperm parameters.

Published
2022

44. SERPINA5 promotes tumour cell proliferation by modulating the PI3K/AKT/mTOR signalling pathway in gastric cancer

Author

Meiyang Fan, Xiaofan Xiong, Lin Han, Lingyu Zhang, Shanfeng Gao, Liying Liu, Xiaofei Wang, Chen Huang, Dongdong Tong, Juan Yang, Lingyu Zhao, and Yuan Shao

Subjects
Gene Expression Regulation, Neoplastic, Phosphatidylinositol 3-Kinases, Carcinogenesis, Stomach Neoplasms, Cell Line, Tumor, TOR Serine-Threonine Kinases, Molecular Medicine, Humans, Cell Biology, Proto-Oncogene Proteins c-akt, Cell Proliferation, Protein C Inhibitor, Signal Transduction
Abstract

SERPINA5 belongs to the serine protease inhibitor superfamily and has been reported to be lowly expressed in a variety of malignancies. However, few report of SERPINA5 in gastric cancer has been found. The purpose of this study was to determine the role of SERPINA5 in GC and to investigate potential tumorigenic mechanisms. We performed qPCR to determine the level of SERPINA5 expression in GC. We used public databases to evaluate whether SERPINA5 could be utilized to predict overall survival and disease-free survival in GC patients. We also knocked down the expression of SERPINA5 and evaluated its effect on cell proliferation and migration. Furthermore, we explored the signal pathways and regulatory mechanisms related to SERPINA5 functions. According to our findings, SERPINA5 was shown to exhibit high expression in GC. Notably, SERPINA5 was prognostic in GC with high expression being unfavourable. SERPINA5 was further observed to promote GC tumorigenesis by modulating GC cell proliferation ability. Mechanically, SERPINA5 could inhibit CBL to regulate the PI3K/AKT/mTOR signalling pathway, thereby promoting GC carcinogenesis progression. These results highlight the important role of SERPINA5 in GC cell proliferation and suggest that SERPINA5 could be a novel target for GC treatment and a predictor for GC prognosis.

Published
2022

45. SERPINA5 may promote the development of preeclampsia by disruption of the uPA/uPAR pathway

Author

Yan Long, Shanshui Zeng, Fei Gao, Fei Liu, Yonggang Zhang, Cheng Zhou, Chunyan Zhu, Xueqin Zhao, Mengru Han, Qiangsheng Gan, Weitao Ye, Fangling Zeng, Chunlin Song, Min Jiang, Gendie E. Lash, and Hongling Yang

Subjects
Placenta, Biochemistry (medical), Public Health, Environmental and Occupational Health, General Medicine, Urokinase-Type Plasminogen Activator, Rats, Receptors, Urokinase Plasminogen Activator, Pre-Eclampsia, Pregnancy, Physiology (medical), Case-Control Studies, Humans, Animals, Female, Protein C Inhibitor
Abstract

Preeclampsia (PE) is the leading cause of maternal and fetal morbidity or mortality but lacks reliable methods for early diagnosis. In a previous study, serum SERPINA5 levels were higher in women with PE before the clinical manifestation of the disease. This study aimed to evaluate the efficacy of SERPINA5 in predicting PE and investigate its role in trophoblast cell biology. A multicenter, 2-stage observational case-control study was performed to develop and validate an early predictive PE model based on SERPINA5, maternal characteristics, and inflammatory factors. To further understand the relationship between SERPINA5 and PE, SERPINA5 was overexpressed or knocked down in extravillous trophoblast cells (EVT) and a pregnant rat model. After development and initial validation, a model that combined SERPINA5 and inflammatory factors had a high predictive ability for PE before 20 weeks gestation with an AUC of 0.90 (95% CI 0.83-0.96). It also demonstrated that SERPINA5 inhibited primary EVT cell invasion by disrupting the urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor (uPA/uPAR) pathway, in turn, is involved in the development of PE. In vivo experiments also proved that overexpression of SERPINA5 induced a PE-like syndrome (hypertension and proteinuria) in pregnant rats. Therefore, serum SERPINA5 is a promising early biomarker of PE, suggesting that it may be involved in placental development through its action on the uPA/uPAR system prior to the clinical manifestation of PE.

Published
2022

46. Cell penetrating SERPINA5 (Protein C inhibitor, PCI): More questions than answers.

Author

Yang, Hanjiang and Geiger, Margarethe

Subjects
*SERPINS, *PLASMINOGEN activator inhibitors, *GLYCOSAMINOGLYCANS, *HEMOSTASIS, *PROTEIN expression, *HUMAN phenotype
Abstract

SERPINA5 (protein C inhibitor, plasminogen activator inhibitor-3) is a secreted, extracellular clade A serpin. Its main characteristics are broad protease reactivity and wide tissue distribution (in man). SERPINA5 has originally been described as an inhibitor of activated protein C and independently as an inhibitor of the plasminogen activator urokinase. SERPINA5 binds glycosaminoglycans, phospholipids, and retinoic acid. Glycosaminoglycans and certain phospholipids can modulate its inhibitory activity and specificity. Studies suggest that SERPINA5 may play a role in hemostasis, in male reproduction, in host defense, and as a tumor suppressor. However, its biological role has not yet been defined. So far SERPINA5 deficiency has not been described in man. Mouse models are of limited value, since in mice serpinA5 is almost exclusively expressed in the reproductive tract. Consistently the only obvious phenotype of serpinA5 -knockout mice is infertility of homozygous males. SERPINA5 can be internalized by cells and translocated to the nucleus. The internalization is dependent on the phospholipid phosphatidylethanolamine and on the intact N-terminus of SERPINA5, which functions as a cell penetrating peptide. Further functional analysis of intracellular SERPINA5 will contribute to our understanding of the biological role of this molecule. [ABSTRACT FROM AUTHOR]

Published
2017
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47. Analysis of Protein C Inhibitor/ SERPINA5

Author

Nejat Akar and Didem Torun Ozkan

Subjects
business.industry, Protein C inhibitor, medicine, General Earth and Planetary Sciences, business, Molecular biology, Protein C, General Environmental Science, medicine.drug
Abstract

Protein C inhibitor is a non-specific serine protease inhibitor with extensive protease reactivity. Protein C inhibitor (SERPINA5, plasminogen activator inhibitor-3/PAI-3) is a secreted, extracellular clade A serpin. SERPINA5/PCI has originally been described as an inhibitor of activated protein C and independently as an inhibitor of the plasminogen activator urokinase. SERPINA5 binds glycosaminoglycans, phospholipids, and retinoic acid. Glycosaminoglycans and certain phospholipids can modulate its inhibitory activity and specificity. PCI plays role at thrombosis and fibrinolysis, regulation of fertilization, tissue regeneration, vascular permeability, tumor development, invasion, metastasis and angiogenesis. In this review; aimed to provide information about the functions of PCI and to provide guidance for studies.

Published
2020

48. A simplified assay for the quantification of circulating activated protein C.

Author

Martos, Laura, Bonanad, Santiago, Ramón, Luis A., Cid, Ana-Rosa, Bonet, Elena, Corral, Javier, Miralles, Manuel, España, Francisco, Navarro, Silvia, and Medina, Pilar

Subjects
*PROTEIN C, *VENOUS thrombosis, *BLOOD plasma, *ENZYME-linked immunosorbent assay, *DETECTION limit
Abstract

Available assays for circulating levels of activated protein C (APC) are either time-consuming or difficult to use in a routine laboratory, or have a detection limit above normal levels. We have developed a simplified assay that measures both the in vivo free APC and the in vivo APC complexed to PC inhibitor (PCI). We measured APC levels, with both assays, in 339 plasma samples, 165 from patients with venous thromboembolism (VTE) and 174 from healthy individuals. The mean APC level in the 339 samples was 0.038 ± 0.010 nM, using a previous assay that measures only the in vivo APC level, and 0.041 ± 0.010 nM with the present new assay. The coefficient of correlation between assays was r = 0.954 ( P < 0.001). The mean APC level in VTE patients was 0.034 ± 0.009 nM (previous assay) and 0.037 ± 0.009 nM (new assay), significantly lower than those in controls ( P < 0.001). In both groups there was a significant correlation between the levels obtained by the two assays ( P < 0.001). These results show that both assays are equivalent, and confirm that the APC level is lower in VTE patients than in healthy individuals. Therefore, the new simplified assay, which measures the sum of circulating free APC and APC complexed to PCI, may be used to estimate the level of circulating APC, and will allow its use in routine laboratories. [ABSTRACT FROM AUTHOR]

Published
2016
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49. Phospholipid Binding Protein C Inhibitor (PCI) Is Present on Microparticles Generated In Vitro and In Vivo.

Author

Einfinger, Katrin, Badrnya, Sigrun, Furtmüller, Margareta, Handschuh, Daniela, Lindner, Herbert, and Geiger, Margarethe

Subjects
*PHOSPHOLIPIDS, *CARRIER proteins, *PROTEIN C inhibitor, *MICROPARTICULATED proteins, *FLOW cytometry
Abstract

Protein C inhibitor is a secreted, non-specific serine protease inhibitor with broad protease reactivity. It binds glycosaminoglycans and anionic phospholipids, which can modulate its activity. Anionic phospholipids, such as phosphatidylserine are normally localized to the inner leaflet of the plasma membrane, but are exposed on activated and apoptotic cells and on plasma membrane-derived microparticles. In this report we show by flow cytometry that microparticles derived from cultured cells and activated platelets incorporated protein C inhibitor during membrane blebbing. Moreover, protein C inhibitor is present in/on microparticles circulating in normal human plasma as judged from Western blots, ELISAs, flow cytometry, and mass spectrometry. These plasma microparticles are mainly derived from megakaryocytes. They seem to be saturated with protein C inhibitor, since they do not bind added fluorescence-labeled protein C inhibitor. Heparin partially removed microparticle-bound protein C inhibitor, supporting our assumption that protein C inhibitor is bound via phospholipids. To assess the biological role of microparticle-bound protein C inhibitor we performed protease inhibition assays and co-precipitated putative binding partners on microparticles with anti-protein C inhibitor IgG. As judged from amidolytic assays microparticle-bound protein C inhibitor did not inhibit activated protein C or thrombin, nor did microparticles modulate the activity of exogenous protein C inhibitor. Among the proteins co-precipitating with protein C inhibitor, complement factors, especially complement factor 3, were most striking. Taken together, our data do not support a major role of microparticle-associated protein C inhibitor in coagulation, but rather suggest an interaction with proteins of the complement system present on these phospholipid vesicles. [ABSTRACT FROM AUTHOR]

Published
2015
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50. Plasma SerpinA5 in conjunction with uterine artery pulsatility index and clinical risk factor for the early prediction of preeclampsia

Author

Yonggang Zhang, Limin Zhao, Hongling Yang, Junzhu Shi, and Yipeng Zhang

Subjects
Embryology, Physiology, Epidemiology, Placenta, Maternal Health, Gastroenterology, Biochemistry, Cohort Studies, Pre-Eclampsia, Pregnancy, Risk Factors, Tandem Mass Spectrometry, Blood plasma, Medicine and Health Sciences, Ultrasonography, Doppler, Color, Enzyme-Linked Immunoassays, Uterine artery, reproductive and urinary physiology, Chromatography, High Pressure Liquid, Protein C Inhibitor, Multidisciplinary, Ultrasound, Obstetrics and Gynecology, Blood proteins, Body Fluids, Trophoblasts, Uterine Artery, Blood, Area Under Curve, Medicine, Biomarker (medicine), Female, Anatomy, Cohort study, Research Article, Adult, medicine.medical_specialty, Science, Enzyme-Linked Immunosorbent Assay, Research and Analysis Methods, Sensitivity and Specificity, Blood Plasma, Preeclampsia, Internal medicine, medicine.artery, medicine, Humans, Immunoassays, Immunohistochemistry Techniques, Plasma Proteins, business.industry, Biology and Life Sciences, Proteins, medicine.disease, Pregnancy Complications, Histochemistry and Cytochemistry Techniques, Pregnancy Trimester, First, Early Diagnosis, ROC Curve, Medical Risk Factors, Immunologic Techniques, Women's Health, Blastocysts, business, Biomarkers, Developmental Biology
Abstract

Object This study aimed to combine plasma protein SerpinA5 with uterine artery doppler ultrasound and clinical risk factor during the first trimester for prediction of preeclampsia. Methods and materials This study was a nested cohort study and was divided into the screening set and developing set. The plasma was collected during the first trimester (11+0–13+6 weeks), at the same time, UtA-PI was detected and recorded with four-dimensional color Doppler ultrasound. These pregnancies were followed up until after delivery. The plasma proteins were examined using ultra-performance liquid chromatography–mass spectrometry (UPLC-MS) and enzyme linked immunosorbent assay (ELISA). Placental samples preserved after delivery were analysed by immunohistochemistry. Clinical risk factors were obtained from medical records or antenatal questionnaires. Upregulation or downregulation of SerpinA5 expression in TEV-1 cells was performed to investigate the role of SerpinA5 in trophoblasts invasion. Results We demonstrated that SerpinA5 levels were greater not only in preeclampsia placental tissue but also in plasma (both p Conclusion These findings showed that placenta-derived plasma SerpinA5 may be a novel biomarker for preeclampsia, which together with uterine artery Doppler ultrasound and clinical risk factor can more effectively predict preeclampsia.

Published
2021

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